Amyotrophic Lateral Sclerosis and History of Skeletal Fracture: A Case-Control Study

For several case-control studies, fractures and mechanical injuries were more frequent among amyotrophic lateral sclerosis (ALS) patients than controls. In the case-control study of Campbell et al, ALS patients displayed 14% more frequent history of fracture; 13% of the cases were diagnosed with disorders of the axial skeleton, compared with 5.4% of the controls. Kurtzke and Beebe, using military records of 504 men who died of ALS, found excess hospital admissions for trauma and fracture, particularly of the limbs and skull. In a study of antecedent events, Kondo and Tsubaki found that mechanical injuries were two to three times more frequent in ALS patients, frequently occurring within 5 years of onset. Our case-control study of suspected risk factors of ALS included assessment of skeletal fractures.

Methods. This study was carried out from January to May 1985. Sampling was done from a case listing developed from the Center for Neurologic Study, a patient support and research facility in San Diego. In addition, letters were sent to area neurologists detailing the goals of the study and seeking to increase case identification.

Identification of cases. (1) Objective diagnostic criteria: clinical picture consisting of (a) progressive mus cular atrophy and weakness, (b) fasciculation, (c) corticospinal tract signs, and (d) no sensory loss. (2) Eligibility criteria: incident cases diagnosed during 1975-1985. Cases included lower and upper motor neuron involvement.

Definition of controls. Friends or neighbors of ALS patients, matched one-to-one on age (+/- 5 years) and sex, not former co-workers, and free of known neurologic disease.

Data collection. Data collection was achieved by means of a mailed, self-administered questionnaire. Sixty ALS cases and 15 surrogates for ALS patients responded; .66 were used after screening for completeness and data quality. There were 33 men (mean age at diagnosis, 55.2) and 33 women (mean age at diagnosis, 57.7). Ninety-seven percent of the cases and controls were white. Each ALS case was given an additional questionnaire to be completed by a friend or neighbor of similar age. Subjects completing the questionnaire responded to demographic items and history of skeletal fracture, date of occurrence, and site of fracture.

Analysis. Retaining matching, McNemar's test was used to test the hypothesis that the odds ratio (OR) was unity for history of having at least one fracture. Ninety-five percent approximate confidence intervals (CI) were constructed.

Results. In comparing the number of individuals who reported at least one fracture, there was no significant difference in ALS cases and controls. Using McNemar's formula for pair matching, the overall OR was 0.88, with a 95% CI of 0.39,1.94. Among men, the OR was 0.90 (Ci= 0.30, 2.67), and among women it was 0.86 (Cl = 0.04, 3.35) (table 1).

Thirty-four (52%) cases reported at least one fracture (15 men, 19 women), compared with 36 (55%) of the control group (16 men and 20 women). Of those cases having a history of skeletal fracture, the mean number of fractures was 1.40 (SD = 0.75), men 1.13 (SD = 0.35) and women 2.47 (SD = 3.39). Among controls, the mean was 1.5 (SD = 0.91), men 1.56 (SD = 0.89) and women 2.25 (SD = 3.59).

Four percent of the ALS patients and 14% of the controls reported fractures involving the head, neck, or spine (table 2). Among cases, 68% of the fractures occurred before diagnosis. Twenty-three percent occurred within 5 years of diagnosis, 19% within 10 years, and 58% more than 10 years before diagnosis. The average number of years from the time of fracture to the time of diagnosis was 24.5 in men (SD = 13.5) and 15.3 in women (SD = 15.0). The average number of years from diagnosis to fracture was 3.8 for men (SD = 2.6) and 2.5 for women (SD = 1.0) (table 3).

Discussion. A number of theories have been proposed concerning the etiology of ALS, especially fractures and disorders of the axial skeleton . Fractures and skeletal abnormalities may imply abnormal mineral metabolism. In particular, the role of Ca++ homeostasis can be seen in hyperparathyroidism, in which a neuromuscular syndrome may be similar to that of ALS. Metabolic abnormalities could prevent proper detoxification of environmental toxins, such as heavy metals. The significance of skeletal demineralization in the pathogenesis of ALS is unclear; different metabolic or toxic factors could be at work. Other factors have also been proposed.

In our investigation of antecedent events of ALS, there was no difference between cases and controls in the number of reported skeletal fractures. The control group reported three times more fractures of the head, neck, and spine region than did ALS cases. Limbs accounted for most fractures in both groups. General trauma was not assessed.

Unlike the findings of Felmus et al, only 16% of the fractures among ALS cases occurred within 5 years of diagnosis. Most were more than 10 years before diagnosis. If susceptibility to an injury is an indication of the early stages of disease, most fractures should occur shortly before onset. Fractures after diagnosis occurred within an average of 3 years. As in the study of Kurtzke and Beebe, there was no predilection for the head, neck, or spine region. In this population, the data did not suggest exposure to skeletal fracture as being a primary etiologic factor in the development of ALS or as serving to promote symptoms.

From the Division of Epidemiology and Biostatistics (Ms. Gresham and Dr. Molgaard), Graduate School of Public Health, and the Department of Mathematical Sciences (Dr. Golbeck), San Diego State University; and the Center for Neurologic Study (Dr. Smith), San Diego, CA.

Received April 28, 1986. Accepted for publication in final form August 5, 1986.

Address correspondence and reprint requests to Ms. Gresham, Division of Epidemiology and Biostatistics, Graduate School of Public Health, San Diego State University, San Diego, CA 92182.

References

1. Campbell AMG, Williams ER, Baritrop D. Motor neuron disease and exposure to lead. J Neurol Neurosurg Psychiatry 1970;3:3:977-985.

2. Kurtzke JF, Beebe GW. Epidemiology of amyotrophic lateral scle osis: a case-control comparison based on ALS deaths. Neurology 1980;30:453-462.

3. Kondo K, Tsubaki T. Case-control studies of motor neuron disease: association with mechanical injuries. Arch Neurol 1981;38:220-226.

4. Gresham LS, Molgaard CA, Golbeck AL, Smith IIA. Amyotrophic lateral sclerosis and occupational heavy metal exposure: a case-control study. Neuroepidemiology 1986; 5:29-38.

5. Johnson N, Kotz S. Distributions in statistics. Boston: Houghton Mifflin Co, 1969.

6. Pierce-Ruhland P., Patten B. Repeat study of antecedent events in motor neuron disease. Ann Clin Res 1981; 13:102-107.

7. FeImus MT, Patten BM, Swanke L. Antecedent events in amytrophic lateral sclerosis. Neurology 1976;26:167-172.

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